While drugs are administered by a wide variety of routes and methods, including oral, oro-transmucosal, buccal, sublingual, via NG-tubes, rectal, intranasal, inhalational, topical, transdermal, intravenous, subcutaneous, intramuscular, epidural and intrathecal, the oral route is by far the most preferred route for most patients and medical settings.
The strong preference and universal acceptance of the oral route include simplicity of drug administration, patient convenience, lower drug costs, and reduced complexity of manufacturing, suitability for repeated and chronic administration and, in many cases, reliable therapeutic effect.
In some cases, drugs need to be administered by a non-oral route. Among the reasons for the use of non-oral routes are lack of therapeutic effect, lack of a consistent, reliable or robust effects, the need for rapid onset of effect, contraindications to oral drug administration, reduced safety by the oral route and the lack of availability of the oral route (for example due to GI obstruction, nausea, vomiting, GI obstruction, obtundation or coma).
Over the past several decades, there have been extensive research, development and commercialization efforts to advance alternatives to orally ingested drug administration, including oro-transmucosal, buccal, sublingual, intranasal, inhalational, topical, transdermal, intravenous, subcutaneous, intramuscular, epidural, intrathecal and transdermal routes. Although there have been remarkable advances in alternatives to orally ingested drugs, the oral route continues to be the preferred route of drug administration, particularly for chronic conditions which frequently require around thr clock amelioration of symptoms.
In many cases, the prediction of absent or significantly poor therapeutic outcomes by the oral route has led to the abandonment of its evaluation through oral ingestion. Such drugs are frequently being used only by a non-oral route (e.g., parenteral route, intranasal or transdermal).
(−)17-(Cyclobutylmethyl)morphinan-3,14-diol (Butorphanol) acts as a partial agonist at μ-opioid receptors and a pure agonist at κ-opioid receptors, with preponderantly antagonist activity at the δ-opioid receptor (Commiskey s, et al, J Pharmacol Sci 2005; 98; 109-116). Its synthesis was first reported in 1973 and has been commercially available in the USA as a parenteral formulation since 1978. It was introduced in the U.S. in parenteral form in 1978 and intranasal form in 1991 (Stadol®). Butorphanol is an infrequently utilized analgesic. Its use is widely relegated to the treatment of acute, self-limiting pain (e.g., migraine, postsurgical pain) where dosing may range from a single dose to a few days of therapy. Butorphanol is almost never used for the treatment of chronic pain for a variety of reasons, including the absence of an oral formulation, the occurrence of sedation, dizziness and psychotomimemtic reactions, the latter attributed to its kappa opioid receptor agonism. Misuse, abuse, addiction and diversion have been reported in humans. Side effects due to kappa opioid receptor agonism generally increase with repeated administration, particularly to individuals with comorbidities.
There are no orally available immediate release formulations of butorphanol for the prevention or treatment of any human ailments. Until now, butorphanol's high incidence of side effects has reduced any desire to develop an oral formulation, which is particularly suited to the treatment of chronic conditions (e.g., chronic pain). In addition, the development and commercialization of oral butorphanol has been impeded by the widely reported poor oral bioavailability. For this reason, pharmaceutical companies have made efforts to develop alternative non-invasive methods of delivering butorphanol into systemic circulation. Foremost among these methods is the intranasal delivery of butorphanol (Stadol®) for the treatment of pain.
Similarly, there are no orally available formulations of modified release or extended release butorphanol. To the applicant's knowledge, no local, state, national or international guidelines, professional society or expert guidelines recommend the use of butorphanol by the oral route in any form (e.g., immediate release form or modified release form), either as a single entity or in combination with other drugs. In addition, even when patients have a suboptimal safety or efficacy response to other opioids, there are no recommendations that butorphanol by the oral route should be among the list of alternatives to be considered (e.g., second or third line therapeutic options). Indeed, even with the commercially intranasal butorphanol, there are no local, state, national or international guidelines, professional society or expert guidelines recommending its use for the treatment of chronic pain
There is a need for oral pharmaceutical compositions of butorphanol which are safe and therapeutically effective.
There is also a need for oral pharmaceutical compositions of butorphanol which have a reduced potential for abuse. Although butorphanol has lower risk of abuse, it does carry a real risk of drug addiction, drug diversion and drug abuse. Reinforcing properties and physical dependence has been demonstrated with butorphanol in experimental models. Unfortunately, when given orally to recreational drug users or addicts, all commercially available immediate release and extended release opioids produce measurable euphoric or psychic effects soon after administration, usually within 15 to 120 minutes. Importantly, recreational opioid users, opioid addicts and patients taking opioids for therapeutic purposes may report different psychic experiences from the same dose of an opioid. Patients taking opioids for therapeutic purposes usually desire the intended benefit (e.g., pain relief) but bemoan the mood altering effects, which may be dysphoric, while recreational opioid users and opioid addicts welcome such mood altering effects. The applicant has found a novel way to deter or minimize the abuse of oral butorphanol among recreational drug users and drug addicts by minimizing the euphoric or psychic effects of the dosage form.
To the applicant's knowledge, (i) the therapeutic benefit of orally ingested butorphanol in modified release form has heretofore not been not been tested or established for any medical condition, including pain, cough, pruritus, dyspnea and other opioid responsive disorders; (ii) no orally ingested controlled release formulations of butorphanol have been has heretofore been developed or commercialized; and (iii) no orally ingested modified release, duodenal release, jejunal release, ileal release, ileo-colonic release, or colonic release formulations of butorphanol have been has heretofore been developed or commercialized.
The applicant has surprisingly discovered that that butorphanol deposited, delivered or made bioavailable distal to stomach, preferably distal to the duodenum, and more preferably, distal to the jejunum or ileum provides significantly more robust therapeutic effects than butorphanol deposited, delivered or made bioavailable proximal to the foregoing anatomic region (e.g., as applicable, proximal to the stomach, duodenum, jejunum or ileum).
The applicant has surprisingly discovered that that butorphanol deposited, delivered or made bioavailable distal to stomach, preferably distal to the duodenum, and more preferably, distal to the jejunum or ileum provides significantly reduced side effects than butorphanol deposited, delivered or made bioavailable proximal to the foregoing anatomic region (e.g., as applicable, proximal to the stomach, duodenum, jejunum or ileum).
The applicant has surprisingly discovered that that butorphanol deposited, delivered or made bioavailable distal to stomach, preferably distal to the duodenum, and more preferably, distal to the jejunum or ileum provides significantly reduced psychotomimetic side effects than butorphanol deposited, delivered or made bioavailable proximal to the foregoing anatomic region (e.g., as applicable, proximal to the stomach, duodenum, jejunum or ileum).
The applicant has surprisingly discovered that that butorphanol deposited, delivered or made bioavailable distal to stomach, preferably distal to the duodenum, and more preferably, distal to the jejunum or ileum reduces the likability and abuse potential of the dosage form than butorphanol deposited, delivered or made bioavailable proximal to the foregoing anatomic region (e.g., as applicable, proximal to the stomach, duodenum, jejunum or ileum).
Butorphanol may be given by the intranasal route. However, intranasal administration has a number of disadvantages, including: (i) the maximum volume and dose of drug that can be delivered by this route of administration, particularly with available formulations; (ii) patient resistance with intranasal administration for systemic therapy, particularly with repeated around the clock dosing; (iii) an increased risk of drug diversion and drug abuse, including intravenous use with liquid forms of abusable drugs; (iv) inability to readily provide prolonged duration of therapy, for example, in extended release dosage forms; (v) lack of dose proportional increases in bioavailability over a wide range of doses and particularly at high doses, thereby limiting clinical utility; (vi) a high peak concentration of butorphanol, which can produce various opioid side effects such as nausea, drowsiness, dizziness and (acute) cognitive impairment.
The dosage form of the invention also provides modified release pharmaceutical compositions and methods of use to improve treatment compliance and to deter episodic, occasional, or intermittent use in subjects requiring chronic butorphanol therapy around the clock or on a time contingent basis by rendering the dosage form therapeutically ineffective or suboptimally effective when taken episodically, intermittently, or occasionally.
The dosage form of the invention also provides pharmaceutical compositions and methods to deter the abuse and misuse of the dosage form by recreational drug users of opioids and opioid addicts by rendering the dosage form devoid of or substantially devoid of euphoria, pleasurable, drug liking or other mood alerting effects when taken on an as needed basis.
The oral route of administration is the most widely used and most widely preferred method of drug administration. It is simple, reliable and readily accessible. Under most conditions of use, particularly outside the hospital setting, it is the recommended method of drug administration. Even in settings of skilled nursing care, where there are resources to initiate and manage parenteral therapy, the goal is to rapidly transition patients from parenteral medications to oral medications. Some generally cited exceptions to the use of the oral route include: (i) drugs with poor oral bioavailability; (ii) drugs requiring a rapid onset of effect; (iii) where venous access already exists (e.g., in the pen-operative or intensive care setting); (iii) where the oral route provides unreliable or inconsistent clinical effects. Therapeutic administration of butorphanol in modified release (e.g., controlled release or delayed onset), duodenal release, jejunal release, ileal release, ileo-colonic release, and colonic release dosage forms has either not been practiced or has been dismissed as unreliable or clinically unacceptable for some of the reasons noted above.
There is a need oral formulations of butorphanol that are therapeutically efficient and that can provide modified release of the butorphanol (e.g, delayed onset, extended release; delayed onset, duodenal delivery; delayed onset, jejunal delivery; delayed onset, ileal delivery; delayed onset, ileo-colonic delivery and delayed onset, colonic delivery).
The applicant has demonstrated for the first time that oral administration of butorphanol in a dosage form that models extended release of butorphanol provides robust therapeutic effects.
The applicant has demonstrated for the first time that oral administration of butorphanol in a dosage form that that models delayed onset, ileo-colonic delivery provides robust therapeutic effects and that this therapeutic effect is more robust than following oral immediate release of butorphanol.
There is therefore a need for new modified release oral pharmaceutical compositions of butorphanol and methods for the treatment of pain, cough, pruritus, dyspnea and other butorphanol responsive medical conditions through targeted gastrointestinal delivery, availability, release, disintegration, dissolution.
Chronic butorphanol therapy can produce a variety of side effects, including drowsiness, dizziness, nausea, vomiting, constipation, psychic effects, mood alteration and cognitive impairment. In subjects under the care of physicians who are highly experienced in pain management in the controlled setting of a clinical trial (where treatment dropout rates should be low), approximately 20 to 40% of subjects discontinue treatment within a few days to a few weeks of initiation of opioid therapy due to side effects. Even after a single dose, intranasal butorphanol produces significant side effects. After intranasal administration of 1 mg or 2 mg butorphanol, side effects included nausea (38%; 46%), vomiting (17%; 17%), dizziness (46%; 58%) and headache (46%; 29%) and oxygen desaturation (3%; 3%). An additional frequently observed side effect of intranasal butorphanol is bad taste in the mouth or the back of throat, and an unpleasant taste immediately after taking the intranasal dose.
For the management of severe pain, the U.S. prescribing information for intranasal butorphanol (Stadol®) provides the option of a 2 mg initial dose (1 mg in each nostril), but requires that this be given only to subjects who “will be able to remain recumbent in the event drowsiness or dizziness occurs”. Therefore, side effects are a substantial deterrent to initiating opioid therapy and they add to patient suffering and the cost of therapy (e.g., drugs to treat the side effects, additional physician visits, etc). There is a need for therapeutically effective formulations of butorphanol which have lower side effects.
Although butorphanol has a mean half-life of about 5 hours, it provides a surprisingly short duration of action following intranasal administration. In a randomized, controlled clinical trial in subjects with acute postsurgical pain receiving the recommended initial of 1 mg intranasal dose of butorphanol, the duration of analgesic effect (as measured by the median time to requesting rescue analgesia) was less than 2 hours. Surprisingly, the duration of analgesic effect in subjects receiving double this dose (2 mg) was also than 2 hours and not significantly different from the 1 mg dose. Even more surprising, about 90% of subjects receiving the usual 1 mg intranasal dose and about 80% of subjects receiving the 2 mg dose required rescue analgesia during the first 6 hours of observation.
There is therefore a need for new pharmaceutical compositions and methods for subjects in need of butorphanol which provide a prolonged duration of therapeutic effect (e.g., more than 6 or 8 hours, preferably more than 12 hours, most preferably at least about 14 hours, 16 hours, 18 hours, 20 hours or 24 hours) when given orally.
Another aspect of the invention provides for resistance of the oral dosage form of the invention to alcohol induced dose dumping. This problem has been documented with several extended release opioid analgesics and can have serious adverse consequences. (Sloan and Babul, Expert Opinion on Drug Delivery 2006; 3:489-97). There is therefore a need for extended release opioids which do not evidence dose dumping in relation to alcohol intake, which do not evidence clinically significant changes in rate or extent of absorption in relation to alcohol intake, which do not evidence clinically significant pharmacodynamic variability in relation to alcohol intake, and which do not evidence bio-inequivalence of the dosage form when given with or without alcohol.
Many commercialized extended release opioids have been shown to have a significant food effect. Another aspect of the invention provides for reduced fed fasted pharmacokinetic variability. An important issue with oral extended release products is its potential for “dose dumping” in relation to food, where the active drug, intended for slow release, is instead released rapidly, resulting in toxicity on the one hand and a decreased duration of effect on the other.
There is therefore a need for extended release opioids which do not evidence dose dumping in relation to food intake, which do not evidence clinically significant changes in rate or extent of absorption in relation to food intake, which do not evidence clinically significant pharmacodynamic variability in relation to food intake, and which do not evidence bio-inequivalence of the dosage form when given in a fed or fasted state.
A pharmaceutically acceptable dosage form of oral butorphanol for the treatment of butorphanol responsive conditions beyond its short duration of action at a controlled rate over an extended period of time appears to be lacking in the pharmaceutical and medical arts.
In view of the foregoing presentation, it is immediately apparent that a serious need exists for an improvement in the delivery of oral butorphanol for its therapeutic effect. The need exists to provide a novel therapeutic composition comprising oral butorphanol, the need exists to provide a novel dosage form comprising oral butorphanol, and the need to provide a novel method of administering butorphanol to a patient in need of butorphanol therapy. The invention provides an oral, relatively easy mode and manner of butorphanol administration in comparison with intranasal and parenteral administration.
To the applicants knowledge, no examples or working prototype formulations of any modified release oral butorphanol have been described in the prior art. Butorphanol is a challenging drug to develop orally due to its high intrinsic clearance and the potential for substantial pharmacokinetic variability.
To the applicant's knowledge, there are no data heretofore demonstrating the efficacy or safety of any oral pharmaceutical compositions of modified release butorphanol
To the applicant's knowledge, there is no prior art on the manufacture, use, efficacy, safety or abuse liability of any delayed onset, duodenal delivery, jejunal delivery, ileal delivery, ileo-colonic delivery or colonic delivery dosage forms of oral butorphanol for the treatment of any butorphanol responsive medical conditions, including pain, cough, pruritus, and dyspnea.
There is a need for new pharmaceutical compositions and methods for the treatment of butorphanol or opioid responsive medical conditions that have high efficacy, good tolerability, are an alternative to the intranasal and parenteral routes, and provide consistent pharmacokinetics and pharmacodynamics.